PROJECT SUMMARY/ABSTRACT The broad goal of the Disease Model Unit (DMU) is to support the generation of new mouse models of human disease in The Jackson Laboratory (JAX) Center for Precision Genetics (JCPG) by providing the facilities and expertise for model-generation pipelines. New models will be generated for six categories of human disease in six separate research projects in the DMU: epileptic encephalopathy, type I diabetes, age-related macular degeneration, chronic kidney disease, Charcot-Marie-Tooth disease, and amyotrophic lateral sclerosis. Model generation will be supported by both leveraging and further specializing the facilities and expertise in existing Scientific Service cores at JAX. Three new cores will be carved out of existing JAX Services: The Genome Editing Core will provide tools for precise genetic engineering; the Behavioral Phenotyping Core will support neurological disease model characterization; and the Viral Vector Custom Design Core will provide Center investigators with custom viral vectors for gene delivery and gene knock-down studies. Other JAX Services will be used that are already sufficiently appropriate and outfitted for the DMU pipeline. While each DMU project will develop its own disease-specific pipeline for model generation, all of them will be supported by the coordination of core resources and expertise provided through the DMU. The Specific Aims of the DMU are: 1) To demonstrate capacity over a range of human conditions, organ systems and ages; 2) to examine common and rare disease; 3) to integrate and fine-tune technologies to the needs of individual research projects, while retaining central efficiency of scale; 4) to emphasize new assays for throughput and efficiency, without losing sight of disease in a native organ system or the intact animal; and 5) to recognize and overcome interspecies differences that are obstacles to further progress. Together with the Center's other major Cores, the DMU- supported pipelines will provide project investigators with the resources and expertise that will ensure generation of models ready for preclinical testing.